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. 2010 Nov;19(11):2859-68.
doi: 10.1158/1055-9965.EPI-10-0517. Epub 2010 Oct 26.

Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Christoph Engel  1 , Beatrix Versmold, Barbara Wappenschmidt, Jacques Simard, Douglas F Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Rebecca Mayes, D Gareth Evans, Rosalind Eeles, Joan Paterson, Carole Brewer; Epidemiological Study of Familial Breast Cancer (EMBRACE); Lesley McGuffog, Antonis C Antoniou, Dominique Stoppa-Lyonnet, Olga M Sinilnikova, Laure Barjhoux, Marc Frenay, Cécile Michel, Dominique Leroux, Helene Dreyfus, Christine Toulas, Laurence Gladieff, Nancy Uhrhammer, Yves-Jean Bignon, Alfons Meindl, Norbert Arnold, Raymonda Varon-Mateeva, Dieter Niederacher, Sabine Preisler-Adams, Karin Kast, Helmut Deissler, Christian Sutter, Dorothea Gadzicki, Georgia Chenevix-Trench, Amanda B Spurdle, Xiaoqing Chen, Jonathan Beesley; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab); Håkan Olsson, Ulf Kristoffersson, Hans Ehrencrona, Annelie Liljegren; Swedish Breast Cancer Study, Sweden (SWE-BRCA); Rob B van der Luijt, Theo A van Os, Flora E van Leeuwen; Hereditary Breast and Ovarian cancer group Netherlands (HEBON); Susan M Domchek, Timothy R Rebbeck, Katherine L Nathanson, Ana Osorio, Teresa Ramón y Cajal, Irene Konstantopoulou, Javier Benítez, Eitan Friedman, Bella Kaufman, Yael Laitman, Phuong L Mai, Mark H Greene, Heli Nevanlinna, Kristiina Aittomäki, Csilla I Szabo, Trinidad Caldes, Fergus J Couch, Irene L Andrulis, Andrew K Godwin, Ute Hamann, Rita K Schmutzler; Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
Collaborators, Affiliations

Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Christoph Engel et al. Cancer Epidemiol Biomarkers Prev. 2010 Nov.

Abstract

Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.

Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).

Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers.

Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers.

Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
Forest plots of the study-specific estimates of the per-allele HRs for CASP8 D302H in BRCA1 mutation carriers (endpoints breast and ovarian cancer). The area of the squares is proportional to the inverse of the variance of the estimate. Horizontal lines represent the 95% CIs. The vertical dashed line indicates the overall effect estimate.
See this image and copyright information in PMC

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